Science —

Feedback loop helps your gut manage its helpful bacteria

The small intestine has a system that keeps its surface free of bacteria, …

We tend to get overly focused on bacteria that are trying to kill us (and there's no shortage of those), but there are large populations of bacteria that live in or on us without causing any problems, and some of them are even helpful. This is especially true in the gut, where bacteria help us with the food we eat and provide some essential nutrients; there's even evidence that our gut bacteria can influence our behavior. This creates a bit of a challenge for the immune system, which needs to kill harmful bacteria and avoid killing helpful ones—but still keep their numbers in check. This involves a degree of interaction between the immune system and the bacteria.

A study in yesterday's Science has described a new way that the gut and bacteria interact to keep things from getting out of hand. Cells in the gut sense when the bacteria get too close, and produce a peptide that kills some of them off when they do. This keeps the space around the cells of the small intestine free of bacteria, which in turn keeps the bacteria from setting off a full-blown immune response.

Gut bacteria (green) keep a safe distance from the surface of the intestine (blue).

Shipra Vaishnava and Laura Hooper.

The research started out with a fairly simple observation. The small intestine, which is covered in tiny, finger-like projections, does not have a physical barrier to prevent bacteria from reaching it. But the bacteria don't manage to get in between the fingers; in fact, as the image above shows, they're generally kept a safe distance away from the surface.

The researchers reasoned that something must be recognizing all the bacteria, not simply specific species, in order to manage that sort of ordering. So they focused on the innate immune system (which recently earned two people a Nobel Prize). This system has a few receptors that recognize features common to all bacteria, allowing it to respond to most of the ecosystem that lives in our guts.

To test this hypothesis, the researchers knocked out the mouse version of a gene that encodes a protein that acts downstream in the signaling pathway triggered by these immune receptors. With the protein (MyD88, for the curious) gone, there was a large increase in the number of bacteria that ended up at the intestinal surface. With that hypothesis confirmed, the researchers turned to the question of how the innate immune system actually kept the bacteria away. To do this, they knocked the same gene out in specific cell types to determine which cells actually sensed the presence of nearby bacteria. With the cells identified, they looked into some of the antibacterial genes known to be expressed there.

They settled on a protein called RegIIIγ, which can kill a broad spectrum of bacteria. It was expressed in the right cells, and knocking out the innate immune system led to a decrease in its expression. The authors knocked the gene for RegIIIγ out as well, and showed that the mice that lacked this protein also had bacteria growing near the surface of the intestine.

So the innate immune system seems to act to keep the bacteria at a safe distance from the surface of the intestine, which probably helps limit infections. But it seems to have a second effect, one that's good for both the bacteria and the host: it keeps the immune system from bringing out its big guns. In the RegIIIγ knockout animals, the surface of the intestine has much higher levels of antibody-producing cells and T cells. These are key players in the adaptive immune system, and suggest the mice mount a full-blown immune response when the bacteria start appearing at the intestinal surface.

Thus, the bacteria and the innate immune system appear to cooperate to keep a full immune response from occurring.

But the authors also note that the full story is even more complicated than this. The RegIIIγ protein is only effective against a subset of the bacteria that live in the gut (the gram-positive ones). But the innate immune system seems to keep all types of bacteria in check, suggesting there are other pathways that target different species. The team involved in this work is undoubtedly looking for those other pathways now.

Don't hop on the S. boulardii bandwagon yet. There's not a ton of data in its favor that I've seen, and most of it is from one group that particularly champions it as a probiotic.

I will let you know in 2 or 3 months, what I actually think. I am pretty much skeptical of everything in Crohn's treatment. Back 15+ years ago when I used to actually take meds all they did is make me puke in new and interseting colors. I ended up having to go under the knife and since then have had no remissions to speak off; but I have been getting kind of sick lately, so I bought a bottle of the stuff to take that should last me a bit. I will judge based on what it does for me. It was basically free since I had an amazon gift card that was given to me, so what can it hurt really.

I think the implication here is that by preventing all bacteria from getting too close to certain gut tissues, the body does not initiate a large immune response to fight the bacteria. Which means that helpful bacteria can do their stuff without harming our health or triggering harmful immune responses.

Here's a bad analogy (sorry, I don't have any good ones). Ozone is good for life if it is high in the sky, shielding us from dangerous UV radiation. Ozone is bad for life if it is a part of ground-level smog and is right next to us so we can breath it into our lungs. Here is a good thing that is bad if it is too close to vulnerable components.

Don't hop on the S. boulardii bandwagon yet. There's not a ton of data in its favor that I've seen, and most of it is from one group that particularly champions it as a probiotic.

I will let you know in 2 or 3 months, what I actually think. I am pretty much skeptical of everything in Crohn's treatment. Back 15+ years ago when I used to actually take meds all they did is make me puke in new and interseting colors. I ended up having to go under the knife and since then have had no remissions to speak off; but I have been getting kind of sick lately, so I bought a bottle of the stuff to take that should last me a bit. I will judge based on what it does for me. It was basically free since I had an amazon gift card that was given to me, so what can it hurt really.

Various probiotics evolved with various humans around the world, which is why we have so many different kinds. One doctor doing blood-type research theorized that certain probiotics were better or worse for different people, depending on genetic factors, blood types, etc. A probiotic that's great for one person can be adverse to another.

Dietary habits should also be taken into consideration. Some groups of humans evolved on high protein / high-fat diets while others became agrarian and ate more carbs. When we have more access to carbs (esp seasonal carbs, like fruit, which mother nature used to regulate our access to), it can cause folks to disrupt their bowel environment into something their natural diet wouldn't cause nor their body adapted to handle.

Ok ... here's some hoke for you, too. There's a rumor that Archway Coconut Macarroon cookies help folks with crohn's. It could be due to the caprillyc acids from the coconut helping to keep bacteria / yeast in check or ... who knows. But, some folks swear by them. Maybe just macaroons in general would help? I don't know. If you've had crohns for so long, I'm assuming you've already tried various things, regardless of how quacky they sound. (No offense).

I do wonder if saying "cooperating" seems inappropriate, as it suggests the bacteria possess a greater sense of agency. Nothing in this research, as I understand it, indicates that the bacteria have learned to *avoid* the intestinal lining. Rather, there is a set of simple, effective, broad-spectrum antibacterial mechanisms that keep the zone clear without triggering a full-blown immune response. It's a well-maintained, actively policed fence.

The bacteria don't know there's an invisible fence there. The fence just kills off most of them that happen to cross the line. Their "cooperation" (and here I'm speculating) is that they've evolved to respect that fence -- to be, or to continue to be susceptible to its defense mechanisms. They exist in a symbiotic relationship with a host; this susceptibility is beneficial in the long run since any bacteria that aren't susceptible will tend to provoke a greater immune response that will either kill them off more thoroughly, weaken the host, or both... so such aberrations should tend to be short-lived.

Aside: there's a subtle problem with the "gut bacteria can influence our behavior" link in the article. The correct URL contains "-–-" ... that's hyphen, en dash (&#x2013; or &ndash;), hyphen ... not just three hyphens in a row, which is what the article is currently linking to (and which results in an error 404).

My 94yo Mother-in-Law has been fighting a C. diff. for 8 months (following antibiotics for a urinary tract infection), and I've been learning a lot about gut bacteria. (Samuel Johnson said "when a man knows he is to be hanged in a fortnight, it concentrates his mind wonderfully." -- well let me tell you, the possible return of explosive diarrhea can do the same.)

Somehow, the immune system cooperates with the "good bacteria" to keep C. difficile under control. That control can fail with damage to either of the two. So I would hold this out as an example of cooperation.

The fact that cooperation and competition have mechanisms and are not the product of consciousness does not invalidate the use of those terms. This research does not show the bacteria are avoiding the RegIIIγ or that the gut is continually producing it. We don't know what it is the bacteria detect near the gut wall that they've learned to avoid, but it does appear they avoid it, rather than simply that they're continually slaughtered whenever they get near.